107Yang Y, et al. Stroke and Vascular Neurology 2018;3:e000168. doi:10.1136/svn-2018-000168
Open access
Dual versus mono antiplatelet therapy for acute non-cardioembolic ischaemic stroke or transient ischaemic attack: a systematic review and meta-analysisYingying Yang,1,2,3,4 Mengyuan Zhou,1,2,4,3 Xi Zhong,1,2,4,3 Yongjun Wang,1,2,4,3 Xingquan Zhao,1,2,4,3 Liping Liu,1,2,4,3 Yilong Wang1,2,4,3
1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China2China National Clinical Research Center for Neurological Diseases, Beijing, China3Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China4Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
Correspondence toProfessor Yilong Wang; yilong528@ aliyun. com
To cite: Yang Y, Zhou M, Zhong X, et al. Dual versus mono antiplatelet therapy for acute non-cardioembolic ischaemic stroke or transient ischaemic attack: a systematic review and meta-analysis. Stroke and Vascular Neurology 2018;3: e000168. doi:10.1136/svn-2018-000168
► Additional material is published online only. To view please visit the journal online (http:// dx. doi. org/ 10. 1136/ svn- 2018- 000168).
Received 31 May 2018Accepted 31 May 2018
► http:// dx. doi. org/ 10. 1136/ svn- 2018- 000171
Original article
© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
AbsTrACTObjective Recent years have seen new evidence on the efficacy and safety of dual antiplatelet therapy for secondary stroke prevention. We updated a meta-analysis of randomised controlled trials evaluating dual antiplatelet versus monotherapy for patients with acute non-cardioembolic ischaemic stroke (IS) or transient ischaemic attack (TIA).Methods We searched PubMed and identified randomised controlled trials evaluating dual antiplatelet versus monotherapy for acute non-cardioembolic IS or TIA within 3 days of ictus up to May 2018. Risk ratio (RR) with 95% CI were calculated using random effects models. Clinical endpoints included stroke recurrence, composite vascular events and major bleeding.results 18 randomised controlled trials including 15 515 patients were pooled in the meta-analysis. When compared with monotherapy among patients with acute IS or TIA, dual antiplatelet therapy reduced the risk of stroke recurrence (RR 0.69; 95% CI 0.61 to 0.78; p<0.001) and composite vascular events (RR 0.72; 95% CI 0.64 to 0.80; p<0.001). Dual therapy was associated with a significant increase in the risk of major bleeding (RR 1.77; 95% CI 1.09 to 2.87; p=0.02) when all trial data were combined. However, when all previous trials before the completion of the POINT trial were analysed, dual antiplatelet versus monotherapy was not associated with a significant increase in the risk of major bleeding (RR 1.46; 95% CI 0.77 to 2.75; p=0.25).Conclusions Among patients with acute non-cardioembolic IS or TIA within 3 days of ictus, dual antiplatelet therapy was associated with a reduction in stroke recurrence, and composite vascular events, when compared with monotherapy. However, a significant increase in the risk of major bleeding was observed.
InTrOduCTIOnAcute minor ischaemic stroke (IS) and transient ischaemic attack (TIA) are very common and often lead to disabling events during the first few weeks.1 Antiplatelet therapy can significantly reduce the risk of vascular events among high-risk patients. Current guidelines strongly recommend early administration of aspirin in patients with acute IS.2 However, the efficacy and
safety of dual antiplatelet therapy have not been fully understood.
Over the past few decades, some large randomised controlled trials (RCT) have shown that dual antiplatelet therapy is more effective in reducing the risk of cerebral embolisation, including the CARESS trial (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis) and CLAIR trial (Clopidogrel plus aspirin vs aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis).3 4 The CHANCE trial (Clopidogrel in High-Risk Patients with Acute Non-Disabling Cerebrovascular Events) further demonstrated that early dual antiplatelet therapy for 21 days among 5170 Chinese patients with non-cardioembolic IS or TIA was efficacious and safe.5 6
A previous meta-analysis including 9012 patients from CHANCE and 13 other RCTs up to November 2012 showed that early dual versus mono antiplatelet therapy within 3 days of symptom onset was more effective in reducing stroke recurrence (risk ratio (RR) 0.69; 95% CI 0.60 to 0.80; p<0.001) and the composite outcome of stroke, TIA, acute coronary syndrome and all death (RR 0.71; 95% CI 0.63 to 0.81; p<0.001), without signifi-cantly increasing the risk of major bleeding (RR 1.35; 95% CI 0.70 to 2.59, p=0.37).7 The 2018 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend the combination of clopidogrel and aspirin among patients with minor IS or TIA for early secondary stroke prevention (Class of recommendation: II A).2 However, considering that the generalisability of the intervention in non-Asian populations remains unclear, the use of dual antiplatelet therapy was only modestly recommended.
Five years after the results of CHANCE were published, POINT (Platelet-Oriented
on June 11, 2020 by guest. Protected by copyright.
http://svn.bmj.com
/S
troke Vasc N
eurol: first published as 10.1136/svn-2018-000168 on 26 June 2018. Dow
nloaded from
108 Yang Y, et al. Stroke and Vascular Neurology 2018;3:e000168. doi:10.1136/svn-2018-000168
Open access
Inhibition in New TIA and Minor Ischemic Stroke), a large double-blind RCT aiming to test the dual anti-platelet therapy with clopidogrel plus aspirin worldwide, has recently published its results.8 9 Therefore, in order to fully explore the efficacy and safety of early dual anti-platelet therapy for secondary stroke prevention, we updated the previous systematic review and meta-anal-ysis of dual versus mono antiplatelet therapy for patients with acute non-cardioembolic IS or TIA within 3 days of symptom onset.7
MeThOdssearch strategyWe updated the previous systematic review and meta-anal-ysis published in Circulation in 20 137 and 14 eligible studies up to November 2012 were included in this current meta-analysis. We also identified RCTs evaluating dual versus mono antiplatelet therapy for acute non-car-dioembolic IS or TIA from November 2012 to May 2018. We searched PubMed and other databases with search words of ‘antiplatelet therapy’, ‘aspirin’, ‘clopidogrel’, ‘cilostazol’, ‘dipyridamole’, ‘ticlopidine’, ‘prasugrel’, ‘triflusal’, ‘glycoprotein IIb/IIIa receptor antagonists’, ‘ticagrelor’, ‘stroke’, ‘cerebral ischemia’, ‘cerebral infarction’, ‘TIA’, ‘transient ischemic attack’, ‘rand-omized controlled trial’ and ‘randomized trial’. We also performed manual search of references from original articles and pertinent reviews. Searches were restricted to completed trials in human beings and English.
selection criteriaTwo independent authors (YY and MZ) selected all studies. Inclusion criteria for the studies were: (1) RCT in design; (2) dual versus mono antiplatelet therapy was assessed in adult patients (≥18 years) with non-cardioembolic IS or TIA; (3) enrolment and randomisation of all or at least a portion of the patients was within 3 days of the index event; (4) at least one of clinical endpoints was assessed, including stroke recurrence, composite vascular events or major bleeding. Stroke recurrence was mostly defined as ischaemic or haemorrhagic stroke. Composite vascular events were mostly defined as the composite of stroke, TIA, myocardial infarction and death from cardiovascular causes. Major bleeding was mostly defined in accordance with moderate to severe bleeding by the Global Utiliza-tion of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries definition.10
data extraction and quality assessmentFirst, for studies published from November 2012 to May 2018, study quality was independently assessed and data were extracted by two authors (YY and XZ) with the supervision from other authors (YW, XZ, LL). We also repeated data extraction from the 14 studies included in the previous meta-analysis. Unpublished subgroup data from these 14 studies were used directly from the previous meta-analysis. The following data were extracted: publi-cation characteristics, countries or regions of the study,
study centres, blinding, enrolled populations, sample size randomised within 3 days of ictus, treatment groups, onset-to-treatment interval, severity of stroke, treatment duration for dual therapy, quality scale, intention-to treat analysis, completeness of follow-up, and efficacy and safety outcomes. The efficacy outcomes evaluated were stroke recurrence and composite vascular events. The safety outcome was major bleeding.
data synthesis and analysisPrimary analyses were performed for each outcome, with trials subdivided by the different medications assessed. RR and 95% CIs were calculated using random effects models because the interventions, event rates and trial designs were expected to vary. We performed a sensitivity analysis by restricting the analysis to double-blind studies, to test whether the results of the present meta-analysis were sensitive to certain restrictions on the data included. Between-study and between-subgroup heterogeneities were evaluated by calculating the I2 statistic and the Cochrane Q (χ2) statistic. Publication bias of studies with different sample sizes was assessed by performing funnel plots. Two-sided probability values of <0.05 were consid-ered statistically significant. All data were analysed using Cochrane Review Manager (V.5.3).
resulTsselection process and study characteristicsAll 14 studies in the previous meta-analysis were included.3 4 6 11–21 For updated relevant studies from November 2012 to May 2018, database searching and citation tracking of references identified 691 publica-tions (online supplementary figure 1). By reviewing title and abstract, 672 articles were excluded. Nineteen articles were reviewed by full text for details, and 15 of them were excluded: not dual versus mono antiplatelet therapy (n=6), no within 3 days of ictus (n=2), not exact onset-to-treatment interval (n=2), not clinical endpoints (n=1) and duplications (n=4). Therefore, four eligible RCTs published after November 2012 were identified, including POINT 2018, COMPRESS 2016, He et al (2015) and Yi et al (2014).9 22–24 All of them compared clopi-dogrel plus aspirin versus aspirin alone in patients with acute non-cardioembolic IS or TIA.
In total, there were 18 studies with 15 515 patients in the present meta-analysis (table 1), among which 9 were double blind, 11 were intention to treat and 15 had concealed allocation. Six trials enrolled patients with IS only12 15 19 21 22 24, one trial enrolled patients with TIA only11 and the others enrolled both patients with IS and TIA. Seven trials focused on minor stroke.4 6 9 17 18 21 23 Onset-to-treatment intervals were ≤1 day in five trials,6 9 16 18 20 ≤2 days in four trials15 21 22 24 and ≤3 days in the other trials. For those trials that had a recruitment window extending beyond 3 days after the index event, we only used data from those patients recruited and randomised within the 3-day time window.3 13 14 16 17
on June 11, 2020 by guest. Protected by copyright.
http://svn.bmj.com
/S
troke Vasc N
eurol: first published as 10.1136/svn-2018-000168 on 26 June 2018. Dow
nloaded from
109Yang Y, et al. Stroke and Vascular Neurology 2018;3:e000168. doi:10.1136/svn-2018-000168
Open access
Tab
le 1
D
esig
n an
d b
asel
ine
char
acte
ristic
s of
incl
uded
tria
ls
Tria
lD
ual t
hera
py
Mo
noth
erap
yD
urat
ion
for
dua
l the
rap
yTr
eatm
ent
ons
etP
atie
nts
Sev
erit
y o
f st
roke
Co
untr
yS
ize
(<3
day
s)B
lind
ing
ITT
ana
lysi
sLo
st t
o f
ollo
w-
up (%
)Q
ualit
y
PO
INT
2018
9C
lop
(600
mg
load
, 75
mg
once
dai
ly)+
Asp
(50–
325
mg
once
dai
ly)
Asp
3 m
onth
s≤1
2 ho
urs
Min
or
IS, T
IAN
IHS
S≤3
Wor
ldw
ide,
269
cent
res
4881
Dou
ble
blin
dIT
T6.
6A
CO
MP
RE
SS
2016
22C
lop
(75
mg
once
dai
ly
with
out
load
)+A
sp (3
00 m
g lo
ad, 1
00 m
g on
ce d
aily
)
Asp
30 d
ays
≤2 d
ays
ISU
NK
Kor
ea, 2
0 ce
ntre
s35
8D
oub
leb
lind
ITT
6.7
A
He
et a
l23C
lop
(300
mg
load
, 75
mg
once
dai
ly)+
Asp
(100
mg
once
dai
ly)
Asp
(300
mg
once
dai
ly)
14 d
ays
≤3 d
ays
Min
or
IS, T
IAN
IHS
S ≤
7C
hina
, sin
gle
cent
re69
0U
NK
Ana
lyse
d a
s tr
eate
d6.
2A
Yi e
t al
24C
lop
(75
mg
once
dai
ly)+
Asp
(200
mg)
fo
r 30
day
s, t
hen
Clo
p
alon
e (7
5 m
g on
ce d
aily
)
Asp
(200
mg
once
dai
ly
for
30 d
ays,
the
n 10
0 m
g on
ce d
aily
)
30 d
ays
≤2 d
ays
ISN
IHS
S ≤
12C
hina
,tw
o ce
ntr e
s57
4B
lind
ed
outc
ome
Ana
lyse
d a
s tr
eate
d0.
7A
CH
AN
CE
2012
6C
lop
(300
mg
load
, 75
mg
once
dai
ly)+
Asp
(75–
300
mg
load
, 75
mg
once
dai
ly) f
or 2
1 d
ays,
th
en C
lop
alo
ne (7
5 m
g)
Asp
(75–
300
mg
load
, 75
mg
once
dai
ly) f
or 3
m21
day
s≤2
4 ho
urs
Min
or
IS, T
IAN
IHS
S ≤
3C
hina
,11
4 ce
ntre
s51
70D
oub
leb
lind
ITT
0.7
A
Nak
amur
a et
al
21C
ilo (1
00 m
g tw
ice
dai
ly)+
Asp
(300
mg,
th
en 1
00 m
g on
ce d
aily
)
Asp
6 m
onth
s≤2
day
sM
inor
ISN
IHS
S ≤
7Ja
pan
, sin
gle
cent
re76
UN
KO
n-tr
eatm
ent
anal
ysis
16.7
B
CLA
IR20
104
Clo
p (3
00 m
g lo
ad, 7
5 m
g on
ce d
aily
)+A
sp (7
5–16
0 m
g on
ce d
aily
)
Asp
7 d
ays
≤3 d
ays
Min
or
IS, T
IAN
IHS
S ≤
8A
sia,
mul
ticen
tres
98B
lind
ed
outc
ome
ITT
1.0
A
PR
oFE
SS
20
0919
Dip
(200
mg
twic
e d
aily
)+A
sp (2
5 m
g tw
ice
dai
ly)
Clo
p (7
5 m
g on
ce d
aily
)3
mon
ths
≤3 d
ays
ISm
RS
0–3
Wor
ldw
ide,
695
cent
res
1360
Dou
ble
blin
dIT
T0.
9A
EA
RLY
2009
20D
ip (2
00 m
g tw
ice
dai
ly)+
Asp
(25
mg
twic
e d
aily
) for
3 m
onth
s
Asp
(100
mg
once
dai
ly)
for
7 d
ays,
the
n D
ip (2
00 m
g tw
ice
dai
ly)+
Asp
(25
mg
twic
e d
aily
)
3 m
onth
s≤2
4 ho
urs
IS, T
IAN
IHS
S ≤
20G
erm
any,
46 c
entr
es54
3B
lind
ed
outc
ome
Ana
lyse
d a
s tr
eate
d2.
9A
FAS
TER
2007
18C
lop
(300
mg
load
, 75
mg
once
dai
ly)+
Asp
(162
mg,
th
en 8
1 m
g on
ce d
aily
)
Asp
3 m
onth
s≤2
4 ho
urs
Min
or
IS, T
IAN
IHS
S ≤
3N
orth
Am
eric
a,18
cen
tres
392
Dou
ble
blin
dIT
T1.
8A
ES
PR
IT20
0617
Dip
(200
mg
twic
e d
aily
)+A
sp (3
0–32
5 m
g on
ce d
aily
)
Asp
42 m
onth
s≤3
day
sM
inor
IS
, TIA
mR
S ≤
3W
orld
wid
e,86
cen
tres
95O
pen
ITT
3.8
A
CH
AR
ISM
A20
0616
Clo
p (7
5 m
g on
ce d
aily
)+A
sp (7
5–16
2 m
g on
ce d
aily
)
Asp
28 m
onth
s≤2
4 ho
urs
IS, T
IAU
NK
Wor
ldw
ide,
768
cent
res
216
Dou
ble
blin
dIT
T≤0
.5A
Cha
irang
sarit
et a
l15D
ip (2
25 m
g on
ce d
aily
)+A
sp (3
00 m
g on
ce d
aily
)
Asp
6 m
onth
s≤2
day
sIS
UN
KTh
aila
nd, s
ingl
e ce
ntre
38O
pen
UN
KU
NK
A
CA
RE
SS
2005
3C
lop
(300
mg
load
, 75
mg
once
dai
ly)+
Asp
(75
mg
once
dai
ly)
Asp
7 d
ays
≤3 d
ays
IS, T
IAN
IHS
S<2
2E
urop
e,11
cen
tres
25D
oub
leb
lind
ITT
0A
Con
tinue
d
on June 11, 2020 by guest. Protected by copyright.
http://svn.bmj.com
/S
troke Vasc N
eurol: first published as 10.1136/svn-2018-000168 on 26 June 2018. Dow
nloaded from
110 Yang Y, et al. Stroke and Vascular Neurology 2018;3:e000168. doi:10.1136/svn-2018-000168
Open access
The following antiplatelet medications were assessed in the meta-analysis: aspirin+clopidogrel versus aspirin (nine trials with 12 404 patients)3 4 6 9 16 18 22–24; aspir-in+clopidogrel versus clopidogrel (one trial with 491 patients)14; aspirin+dipyridamole versus aspirin (five trials with 964 patients)12 13 15 17 20; aspir-in+dipyridamole versus dipyridamole (two trials with 220 patients)11 13; aspirin+dipyridamole versus clopidogrel (one trial with 1360 patients)19; and cilostazol+aspirin versus aspirin (one trial with 76 patients).21 The European Stroke Prevention Study 2 investigated the combination of aspirin and dipyrida-mole against aspirin alone and dipyridamole alone, and the other studies each investigated one antiplatelet in the monotherapy group. No studies involving prasu-grel, ticlopidine, ticagrelor or triflusal were identified.
synthesis of resultsFor analyses of efficacy and safety outcomes, no evidence existed for between-study or between-subgroup heteroge-neities by the Cochrane Q statistic and the I2 statistic. No significant publication bias was identified by visual inspec-tion of asymmetry of the funnel plots.
Sixteen studies had data regarding the efficacy outcome of stroke recurrence. In these 16 studies with different follow-up durations, dual antiplatelet therapy reduced the risk of stroke recurrence by ≈30% in patients with acute IS or TIA, as compared with monotherapy (RR 0.69; 95% CI 0.61 to 0.78; p<0.001; figure 1). Eleven studies had data regarding the composite vascular events. Among these 11 studies, dual antiplatelet therapy significantly reduced the risk of the composite vascular events by ≈30% in patients with acute IS or TIA randomised within 3 days of ictus, when compared with monotherapy (RR 0.72; 95% CI 0.64 to 0.80; p<0.001; figure 2).
Fourteen studies had data regarding the safety outcome of major bleeding. When all trial data were combined, major bleeding occurred in 0.65% and 0.33% of patients in the dual and monotherapy groups, respectively. As compared with mono antiplatelet therapy, dual therapy for patients with acute IS or TIA was associated with a significant increase in the risk of major bleeding (RR 1.77; 95% CI 1.09 to 2.87; p=0.02; figure 3). However, when all previous trials before the completion of the POINT trial were analysed, dual versus monotherapy was not associated with a significant increase in the risk of major bleeding (RR 1.46; 95% CI 0.77 to 2.75; p=0.25; figure 4).
Sensitivity analyses restricted to the nine double-blind trials showed similar results for each outcome (online supplementary table 1) when compared with the full analyses.3 6 9 13 14 16 18 19 22
In the subgroup of the nine RCTs comparing clopi-dogrel plus aspirin versus aspirin alone, eight trials had dual therapy of ≤3 months (7 days to 3 months). When compared with aspirin alone, the combina-tion of clopidogrel and aspirin was associated with a significant reduction in stroke recurrence (RR 0.69; Tr
ial
Dua
l the
rap
yM
ono
ther
apy
Dur
atio
n fo
r d
ual t
hera
py
Trea
tmen
t o
nset
Pat
ient
sS
ever
ity
of
stro
keC
oun
try
Siz
e(<
3 d
ays)
Blin
din
gIT
T a
naly
sis
Lost
to
fo
llow
-up
(%)
Qua
lity
MAT
CH
2004
14C
lop
(75
mg
once
dai
ly)+
Asp
(75
mg
once
dai
ly)
Clo
p18
mon
ths
≤3 d
ays
IS, T
IAm
RS
0–5
Wor
ldw
ide,
507
cent
res
491
Dou
ble
blin
dIT
T4
A
ES
PS
219
9613
Dip
(200
mg
twic
e d
aily
)+A
sp (2
5 m
g tw
ice
dai
ly)
Asp
or
Dip
24 m
onth
s≤3
day
sIS
, TIA
mR
S 0
–5E
urop
e,59
cen
tres
221
Dou
ble
blin
dIT
T0.
64A
Kay
e12D
ip+
Asp
(900
mg
once
dai
ly)
Asp
UN
K≤3
day
sIS
UN
KU
NK
178
UN
KU
NK
UN
KB
Mat
ías-
Gui
u et
al
11D
ip (1
00 m
g fo
ur t
imes
d
aily
)+A
sp (5
0 m
g on
ce d
aily
)
Dip
21.4
≤3 d
ays
TIA
UN
KS
pai
n, s
ingl
e ce
ntre
109
Op
enU
NK
4.5
B
Qua
lity
scal
e: A
, tru
e ra
ndom
isat
ion
and
allo
catio
n co
ncea
led
; B, p
roce
ss o
f ran
dom
isat
ion
not
give
n an
d c
once
alm
ent
of a
lloca
tion
uncl
ear.
Asp
, asp
irin;
Cilo
, cilo
staz
ol; C
lop
, clo
pid
ogre
l; D
ip, d
ipyr
idam
ole;
IS, i
scha
emic
str
oke;
ITT
inte
ntio
n to
tre
at; m
RS
, mod
ified
Ran
kin
Sca
le; N
IHS
S, N
atio
nal I
nstit
utes
of H
ealth
Str
oke
Sca
le; T
IA, t
rans
ient
isch
aem
ic
atta
ck; U
NK
, unk
now
n.
Tab
le 1
C
ontin
ued
on June 11, 2020 by guest. Protected by copyright.
http://svn.bmj.com
/S
troke Vasc N
eurol: first published as 10.1136/svn-2018-000168 on 26 June 2018. Dow
nloaded from
111Yang Y, et al. Stroke and Vascular Neurology 2018;3:e000168. doi:10.1136/svn-2018-000168
Open access
95% CI 0.61 to 0.79; p<0.001; figure 1), as well as the composite vascular events (RR 0.71; 95% CI 0.63 to 0.80; p<0.001; figure 2), and there was significant increase in major bleeding (RR 1.88; 95% CI 1.08 to 3.28; p=0.03; figure 3).
The other combinations of dual antiplatelet therapy analysed did not significantly reduce risks of stroke recurrence or the composite vascular events, as compared with monotherapy (figures 1 and 2),
though there were no significant between-subgroup heterogeneities throughout the analyses. For trials comparing aspirin plus dipyridamole versus aspirin alone, there were no significant differences between dual antiplatelet therapy and monotherapy on stroke recurrence (RR 0.64; 95% CI 0.37 to 1.10; p=0.11; figure 1), composite vascular events (RR 0.67; 95% CI 0.42 to 1.07; p=0.09; figure 2) and major bleeding (RR 0.92; 95% CI 0.06 to 14.61; p=0.95; figure 3).
Figure 1 Comparison of dual antiplatelet versus monotherapy in acute ischaemic stroke or transient ischaemic attack on stroke recurrence. A, aspirin; C, clopidogrel; D, dipyridamole; M-H, Mantel-Haenszel method.
on June 11, 2020 by guest. Protected by copyright.
http://svn.bmj.com
/S
troke Vasc N
eurol: first published as 10.1136/svn-2018-000168 on 26 June 2018. Dow
nloaded from
112 Yang Y, et al. Stroke and Vascular Neurology 2018;3:e000168. doi:10.1136/svn-2018-000168
Open access
dIsCussIOnIn this updated systematic review and meta-analysis, 18 RCTs (15 515 patients) evaluating dual versus mono antiplatelet therapy for acute non-cardioembolic IS or TIA within 3 days of ictus were included. We found that, compared with monotherapy, dual antiplatelet therapy was associated with a reduction in stroke recurrence, and composite vascular events, but with a significant increase in the risk of major bleeding. It is likely that good blood pressure control would markedly reduce the risk of intracranial haemorrhage, and diagnosis and treatment
of Helicobacter pylori would markedly reduce the risk of major gastrointestinal haemorrhage.
A sensitivity analysis restricted to the nine double-blind RCTs showed similar results, which indicated that results of the present meta-analysis were generalisable. For each outcome, no significant between-study or between-sub-group heterogeneity in treatment effects of dual versus mono antiplatelet therapies was found. The effect of dual antiplatelet therapy on efficacy outcomes in the present meta-analysis was consistent with the results of POINT and CHANCE, while the effect on the safety outcome of
Figure 2 Comparison of dual antiplatelet versus monotherapy in acute ischaemic stroke or transient ischaemic attack on composite outcome of stroke, transient ischaemic attack, acute coronary syndrome and all death. A, aspirin; C, clopidogrel; D, dipyridamole; M-H, Mantel-Haenszel method.
on June 11, 2020 by guest. Protected by copyright.
http://svn.bmj.com
/S
troke Vasc N
eurol: first published as 10.1136/svn-2018-000168 on 26 June 2018. Dow
nloaded from
113Yang Y, et al. Stroke and Vascular Neurology 2018;3:e000168. doi:10.1136/svn-2018-000168
Open access
major bleeding was not consistent with the overall esti-mate of all previous trials before POINT.
Both CHANCE and POINT are large randomised, double-blind, placebo controlled, multicentre trials designed to investigate the efficacy and safety for clopido-grel plus aspirin versus aspirin alone in patients with acute minor IS or TIA. However, these two RCTs have some key differences in design. First, the enrolled populations are different. POINT enrolled patients within 12 hours of symptom onset mainly in American and European countries, while CHANCE only enrolled Chinese patients
within 24 hours of symptom onset. Second, the antiplatelet therapy adopted in two trials is different. The treatment duration for dual antiplatelet therapy in POINT is 90 days, while the duration in CHANCE is 21 days. Also, the loading dose of clopidogrel in POINT is 600 mg, while the loading dose in CHANCE is 300 mg. Third, the primary efficacy outcome in POINT is a composite of major isch-aemic events (IS, myocardial infarction or death from an ischaemic vascular event), while it is stroke (ischaemic or haemorrhagic) in CHANCE. Both trials showed the combination of clopidogrel with aspirin could reduce
Figure 3 Comparison of dual antiplatelet versus monotherapy in acute ischaemic stroke or transient ischaemic attack on major bleeding. A, aspirin; C, clopidogrel; D, dipyridamole; M-H, Mantel-Haenszel method.
on June 11, 2020 by guest. Protected by copyright.
http://svn.bmj.com
/S
troke Vasc N
eurol: first published as 10.1136/svn-2018-000168 on 26 June 2018. Dow
nloaded from
114 Yang Y, et al. Stroke and Vascular Neurology 2018;3:e000168. doi:10.1136/svn-2018-000168
Open access
the risk of stroke recurrence. Therefore, the results of POINT broaden the results of CHANCE to more diverse populations and care setting. However, there was a rate of major haemorrhage of 0.9% in combined antiplatelet group of POINT, significantly higher than 0.4% in the aspirin group of POINT, while the rate of moderate to severe haemorrhage in both groups of CHANCE is 0.3%. It seems that the smaller loading dose of clopidogrel and shorter treatment duration for combined clopidogrel plus aspirin may reduce the risk of haemorrhage. In addi-tion, the frequency of CYP2C19 loss-of-function alleles in Asian population is higher than that in other populations, thus reducing the risk of haemorrhage in CHANCE by poor metabolism of clopidogrel.25 26 These comparisons between POINT and CHANCE further suggest adminis-tering short-term dual antiplatelet therapy in the acute phase of IS or TIA is efficacious and safe.27
Another double-blind RCT included in the meta-anal-ysis after November 2012, the COMPRESS trial (Combi-nation of Clopidogrel and Aspirin for Prevention of Recurrence in Acute Atherothrombotic Stroke Study), randomised 358 patients with acute IS caused by large artery atherosclerosis within 48 hours of onset to clopido-grel plus aspirin or to aspirin alone for 30 days.22 However, clopidogrel plus aspirin was not shown to be superior to aspirin alone in reducing new ischaemic lesion recur-rence on MRI and clinical vascular events. Only 21.8% of patients were enrolled within 24 hours of onset and a
loading dose of clopidogrel was not given, both of which might explain the negative results.
The recently published TARDIS trial (Triple Antiplate-lets for Reducing Dependency after Ischaemic Stroke), an international, open-label, blinded-endpoint, superi-ority RCT,28 compared the safety and efficacy of intensive (combined aspirin, clopidogrel and dipyridamole) versus guideline-based (either clopidogrel alone or combined aspirin and dipyridamole) antiplatelet therapy in 3096 patients with acute non-cardioembolic IS or TIA within 48 hours of onset. The TARDIS trial was not included in the present meta-analysis, because it focused on triple versus mono or dual antiplatelet therapy. In TARDIS, triple antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did signifi-cantly increase the risk of major bleeding, suggesting triple antiplatelet therapy should not be used.29
The SOCRATES trial (Acute Stroke or Transient Isch-emic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes) compared ticagrelor with aspirin in an interna-tional population, so it was not included in our meta-anal-ysis.30 The main SOCRATES analysis found that ticagrelor was not superior to aspirin in reducing the risk of major vascular events.31 However, ticagrelor was superior to aspirin in large artery disease,32 and there was a trend to superiority in Asian patients.33 Two other relevant RCTs are ongoing. The international THALES trial (Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and
Figure 4 Comparison of the separate POINT results and the overall estimates of dual antiplatelet versus monotherapy from all other trials included in the present meta-analysis on major bleeding; M-H, Mantel-Haenszel method.
on June 11, 2020 by guest. Protected by copyright.
http://svn.bmj.com
/S
troke Vasc N
eurol: first published as 10.1136/svn-2018-000168 on 26 June 2018. Dow
nloaded from
115Yang Y, et al. Stroke and Vascular Neurology 2018;3:e000168. doi:10.1136/svn-2018-000168
Open access
ASA (acetylsalicylic acid) for Prevention of Stroke and Death) aimed to demonstrate the superior efficacy of tica-grelor plus aspirin versus aspirin alone in the prevention of subsequent stroke at 30 days in patients with IS or TIA ( ClinicalTrials. gov number: NCT03354429). THALES will be covered in an updated meta-analysis like this one. In addition, the CSPS. com trial (Cilostazol Stroke Prevention Study for Antiplatelet Combination), a multicentre, open-label RCT, is evaluating the efficacy and safety of dual anti-platelet therapy involving cilostazol for secondary stroke prevention.34 A total of 4000 high-risk patients with non-car-dioembolic IS will be randomised 8–180 days after onset to dual therapy with cilostazol plus aspirin or clopidogrel, or to aspirin or clopidogrel monotherapy for at least 1 year ( ClinicalTrials. gov identifier: NCT01995370). However, CSPS. com excluded patients within 3 days of ictus.
There are several limitations of the meta-analysis. First, included studies varied in characteristics, including the study population, stroke severity, antiplatelet medications, onset-to-treatment interval, treatment and follow-up dura-tions, and other aspects. All of these factors could be poten-tial confounders. Second, in some included studies, patients with IS or TIA within 3 days of ictus were not the primary target population and were a small portion of the primary study populations. Baseline characteristics might not be well balanced between dual and monotherapy groups in these studies.
COnClusIOnsAmong patients with acute non-cardioembolic IS or TIA within 3 days of ictus, dual antiplatelet therapy was associ-ated with a reduction in stroke recurrence, and composite vascular events, when compared with monotherapy. However, a significant increase in the risk of major bleeding was observed, which might attribute to higher loading dose of clopidogrel and longer treatment duration for dual therapy. The current data suggest administering short-term dual antiplatelet therapy in the acute phase of IS or TIA is efficacious and safe.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.Patient consent Not required.Provenance and peer review Commissioned; internally peer reviewed.data sharing statement Additional data that supports the finding of this study is available from the online supplement.
Guest chief editor J David Spence
Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http:// creativecommons. org/ licenses/ by- nc/ 4. 0/
RefeRences 1. Coull AJ, Lovett JK, Rothwell PM. Oxford Vascular Study. Population
based study of early risk of stroke after transient ischaemic attack or
minor stroke: implications for public education and organisation of services. BMJ 2004;328:326.
2. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2018;49:e46–e99.
3. Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation 2005;111:2233–40.
4. Wong KS, Chen C, Fu J, et al. Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blinded-endpoint trial. Lancet Neurol 2010;9:489–97.
5. Wang Y, Johnston SC. CHANCE Investigators. Rationale and design of a randomized, double-blind trial comparing the effects of a 3-month clopidogrel-aspirin regimen versus aspirin alone for the treatment of high-risk patients with acute nondisabling cerebrovascular event. Am Heart J 2010;160:380–6.
6. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013;369:11–19.
7. Wong KS, Wang Y, Leng X, et al. Early dual versus mono antiplatelet therapy for acute non-cardioembolic ischemic stroke or transient ischemic attack: an updated systematic review and meta-analysis. Circulation 2013;128:1656–66.
8. Johnston SC, Easton JD, Farrant M, et al. Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trial: rationale and design. Int J Stroke 2013;8:479–83.
9. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med 2018.
10. GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673–82.
11. Matías-Guiu J, Dávalos A, Picó M, et al. Low-dose acetylsalicylic acid (ASA) plus dipyridamole versus dipyridamole alone in the prevention of stroke in patients with reversible ischemic attacks. Acta Neurol Scand 1987;76:413–21.
12. Kaye J. A trial to evaluate the relative roles of dipyridamole and aspirin in the prevention of deep vein thrombosis in stroke patients. Boehringer-Ingelheim: Bracknell, 1989.
13. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1–13.
14. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331–7.
15. Chairangsarit P, Sithinamsuwan P, Niyasom S, et al. Comparison between aspirin combined with dipyridamole versus aspirin alone within 48 hours after ischemic stroke event for prevention of recurrent stroke and improvement of neurological function: a preliminary study. J Med Assoc Thai 2005;88 Suppl 3(Suppl 3):S148–54.
16. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706–17.
17. Halkes PH, van Gijn J, Kappelle LJ, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367:1665–73.
18. Kennedy J, Hill MD, Ryckborst KJ, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol 2007;6:961–9.
19. Bath PM, Cotton D, Martin RH, et al. Effect of combined aspirin and extended-release dipyridamole versus clopidogrel on functional outcome and recurrence in acute, mild ischemic stroke: PRoFESS subgroup analysis. Stroke 2010;41:732–8.
20. Dengler R, Diener HC, Schwartz A, et al. Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol 2010;9:159–66.
21. Nakamura T, Tsuruta S, Uchiyama S. Cilostazol combined with aspirin prevents early neurological deterioration in patients with acute ischemic stroke: a pilot study. J Neurol Sci 2012;313:22–6.
22. Hong KS, Lee SH, Kim EG, et al. Recurrent Ischemic Lesions After Acute Atherothrombotic Stroke: Clopidogrel Plus Aspirin Versus Aspirin Alone. Stroke 2016;47:2323–30.
on June 11, 2020 by guest. Protected by copyright.
http://svn.bmj.com
/S
troke Vasc N
eurol: first published as 10.1136/svn-2018-000168 on 26 June 2018. Dow
nloaded from
116 Yang Y, et al. Stroke and Vascular Neurology 2018;3:e000168. doi:10.1136/svn-2018-000168
Open access
23. He F, Xia C, Zhang JH, et al. Clopidogrel plus aspirin versus aspirin alone for preventing early neurological deterioration in patients with acute ischemic stroke. J Clin Neurosci 2015;22:83–6.
24. Yi X, Lin J, Wang C, et al. A comparative study of dual versus monoantiplatelet therapy in patients with acute large-artery atherosclerosis stroke. J Stroke Cerebrovasc Dis 2014;23:1975–81.
25. Wang Y, Zhao X, Lin J, et al. Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack. JAMA 2016;316:70–8.
26. Hasan MS, Basri HB, Hin LP, et al. Genetic polymorphisms and drug interactions leading to clopidogrel resistance: why the Asian population requires special attention. Int J Neurosci 2013;123:143–54.
27. Pan Y, Jing J, Chen W, et al. Risks and benefits of clopidogrel-aspirin in minor stroke or TIA: Time course analysis of CHANCE. Neurology 2017.
28. Krishnan K, Beridze M, Christensen H, et al. Safety and efficacy of intensive vs. guideline antiplatelet therapy in high-risk patients with recent ischemic stroke or transient ischemic attack: rationale and design of the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial (ISRCTN47823388). Int J Stroke 2015;10:1159–65.
29. Bath PM, Woodhouse LJ, Appleton JP, et al. Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or
aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. Lancet 2018;391:850–9.
30. Johnston SC, Amarenco P, Albers GW, et al. Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial: rationale and design. Int J Stroke 2015;10:n/a–8.
31. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack. N Engl J Med 2016;375:35–43.
32. Amarenco P, Albers GW, Denison H, et al. Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial. Lancet Neurol 2017;16:301–10.
33. Wang Y, Minematsu K, Wong KS, et al. Ticagrelor in Acute Stroke or Transient Ischemic Attack in Asian Patients: From the SOCRATES Trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes). Stroke 2017;48:167–73.
34. Toyoda K, Uchiyama S, Hoshino H, et al. Protocol for Cilostazol Stroke Prevention Study for Antiplatelet Combination ( CSPS. com): a randomized, open-label, parallel-group trial. Int J Stroke 2015;10:253–8.
on June 11, 2020 by guest. Protected by copyright.
http://svn.bmj.com
/S
troke Vasc N
eurol: first published as 10.1136/svn-2018-000168 on 26 June 2018. Dow
nloaded from